Switching mechanism for arresting and restarting cancer cell proliferation and migration by the cell adhesion molecule nectin

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16744
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kobe University
• Principal Investigator: Kedashiro Shin 神戸大学, 医学研究科, 特命助教 (00754558)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: ネクチン－４ / ErbB2 / p95-ErbB2 / インテグリンα6β4

Outline of Final Research Achievements

Cancer cell proliferation and migration are essential for onset, progression, and metastasis of cancer, but cancer cells are considered not to proliferate during circulation in blood. The switching mechanism for arresting and restarting cancer cell proliferation remains elusive. The cell adhesion molecule nectin-4 is upregulated in many types of cancers. In this study, we found that nectin-4 interacted with ErbB2 to promote its activation, eventually accelerating breast cancer cell proliferation through the PI3K-AKT signaling pathway. We further found that nectin-4 cis-interacted with p95-ErbB2, a trastuzumab-resistant variant of ErbB2, and cooperatively enhanced a transcription factor SOX2 gene expression and cell proliferation in a suspension culture. Only the combination of nectin-4 and p95-ErbB2 cooperatively activated the Hippo signaling pathway to enhance SOX2 gene expression. Thus, nectin-4 regulates the switching mechanism for arresting and restarting cancer cell proliferation.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

現在、日本では二人に一人はがんに罹患すると言われており、その発症や、がん細胞の転移や生存の仕組みの解明は喫緊の課題である。事実、様々な抗がん剤がその仕組みを標的とし、積極的に開発されている。細胞接着分子ネクチン－４と成長因子受容体ErbB2は、乳がんを含む多くのがんにおいて、その転移や生存を促進するタンパク質として知られている。本研究において、ネクチン－４や薬剤耐性型ErbB2によるがん細胞の増殖機構を解明した。本成果は、ネクチン－４を発現するがん細胞や薬剤耐性型ErbB2に対する新規抗がん剤の開発に役立つと期待される。